Inhaler

ABSTRACT

A dry powder inhaler has a vibrator coupled to a blister filled with a dry powder drug substance. One or more of drug ejection apertures in the blister are substantially opposite the vibrator. One or more air intake apertures in the blister are not opposite the vibrator. Upon vibration of the vibrator, the drug substance is deaggregated, aerosolized, and ejected from the drug ejection apertures for inhalation by a patient.

FIELD OF THE INVENTION

Embodiments of this invention are related to medical devices and drugdelivery devices, specifically to delivery of aerosolized drugs, toinhalation of drugs for delivery to lungs and gastrointestinal tract,and to intranasal drug delivery.

BACKGROUND OF THE INVENTION

Devices for delivery of aerosolized drug substances, including deliveryvia inhalation, are known in the art, examples including U.S. Pat. Nos.5,694,920, 6,026,809, 6,142,146, all by Abrams and Gumaste, U.S. Pat.No. 3,948,264 by Wilke et al., U.S. Pat. No. 6,971,383 by Hickey et al.,U.S. Pat. No. 7,117,867 by Cox et al., U.S. Pat. No. 6,901,929 by Burret al., U.S. Pat. No. 6,779,520 by Genova et al., U.S. Pat. No.6,748,944 by DellaVecchia et al., U.S. Pat. No. 5,590,645 by Davies etal. The above patents also provide an overview of various aerosolizationand inhalation devices and techniques.

A range of aerosolization and inhalation drug delivery devices is known,including metered dose inhalers, nebulizers, dry powder inhalers,thermal vaporizers, and other systems, with differences related tomethods and efficiency of aerosolization and delivery of drug substancesto the patient. Metered dose inhalers are typically using pressurizedgas to aerosolize the drug substance. Disadvantages of these inhalersare related to difficulties to control the delivered dose of the drugsubstance and also to high speed of aerosol particles, resulting inparticles impinging and depositing on various surfaces in the mouth andin the throat of a patient. Inhalation devices delivering drugsubstances as a dry powder are known as dry powder inhalers. Passive drypowder inhalers rely on the patient's inspiratory effort to de-aggregateand aerosolize drug substance for inhalation, while active dry powderinhalers typically input additional energy, such as mechanical orelectrical energy in order to improve the efficiency of powderdeaggregation and aerosolization, to decrease the inspiratory effortneeded from the patient, and to achieve better inspiratory flowindependence of the inhaler performance. Typically for delivery of drugsubstances to the lungs of a patient via inhalation, the drug aerosolparticle size has to be less than about 10 microns, more preferably lessthan about 6 microns, and for delivery to deep lung less than about 3.3microns. Larger size particles will be delivered to the mouth and throatof the patient and as a result will be delivered to the gastrointestinaltract of the patient. There is a need to increase the quantities of adrug that dry powder inhalers are capable of aerosolizing during asingle inhalation by a patient, e.g. within one to three-four seconds.There is also a need to increase the speed of deaggregation andaerosolization of powders by dry powder inhalers.

Dry powder inhalation devices described in U.S. Pat. Nos. 5,694,920,6,026,809, 6,142,146, all by Abrams and Gumaste, utilize vibratory meansto deaggregate and aerosolize dry powder medication for delivery to thepatient as an aerosol. US Patent Publication 2005/0183724 by Gumaste andBowers discloses a synthetic jet-based medicament delivery method andapparatus.

BRIEF DESCRIPTION OF THE INVENTION

Briefly, an embodiment of the invention comprises a device forinhalation of aerosolized drug substances, wherein a high frequencyvibrator is coupled to a container filled with a dry powder drugsubstance. Vibrations of the vibrator result in deaggregating,aerosolizing and ejecting of the drug substance from the container forinhalation by a patient. One or more apertures in the container aresubstantially opposite the vibrator and are used primarily for drugejection, via synthetic jetting or other mechanisms of ejecting thepowder from the container. At least one other aperture in the containeris used primarily for ingress of outside gas or air into the container.

Unexpected results, as illustrated in the examples to follow, wereobtained when performing experimental testing of the embodiments of thepresent invention for use as an inhalation and/or aerosolization device,with observations of substantially faster aerosolization and ejection ofdry powders, as well as capability of aerosolizing substantially largerquantities of dry powders vs. prior art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of an embodiment of the presentinvention showing a container with a drug substance coupled to avibrator.

FIG. 2 is a cross-sectional view of an embodiment of the presentinvention showing a container with a drug substance coupled to avibrator.

FIG. 3 is a cross-sectional view of several embodiments of the presentinvention showing containers with a drug substance coupled to vibrators.

FIG. 4 is a cross-sectional view of an embodiment of the presentinvention showing a container with a drug substance coupled to avibrator.

FIG. 5 is a cross-sectional view of several embodiments of the presentinvention showing containers with a drug substance coupled to vibrators.

FIG. 6 is a cross-sectional view of an embodiment of the presentinvention showing a container with a drug substance coupled to avibrator.

FIG. 7 is a cross-sectional view of embodiments of the present inventionshowing inhalation devices.

FIG. 8 is a cross-sectional view of an embodiment of the presentinvention showing an inhalation device.

FIG. 9 is a cross-sectional view of embodiments of the present inventionshowing inhalation devices.

FIG. 10 is a cross-sectional view of an embodiment of the presentinvention showing an inhalation device.

In the drawings, like numerals refer to like parts or featuresthroughout the several views.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

A cross-sectional view of an embodiment of the present invention isschematically illustrated in FIG. 1. A vibrator 100 is coupled to ablister or container 110 which contains a drug substance or substances120. Vibrator 100 can be a piezo actuator or piezo transducer, or amechanical vibrator, an electromagnetic vibrator, a magnetostrictiveelement, or other vibrating mechanism, as known in the art. In oneembodiment, a piezo actuator is utilized, typically consisting of apiezo ceramic element and a metallic body, of either unimorph or bimorphdesign. Piezo actuator designs known in the art can be used, including,but not limited to, air transducers and piezo-electric sensing elements.Additionally, polymeric piezo materials and actuators based on polymericpiezo materials can be utilized as vibrators. Vibrators based on piezoactuators are energized, as known in the art, by supplying electricpower, typically alternating electric current of appropriate frequenciesand amplitude, to the piezo component. Piezo actuators tuned to variousresonant frequencies can be used, for example with resonant frequenciesin the range from about 1 kHz to about 100 kHz, more typically in theultrasonic range from about 30 kHz to about 45 kHz, and amplitude ofmechanical oscillations from about 1 micron to about 50 microns peak topeak. Vibrator 100 is capable of vibrating, with either fixed orvariable frequency, or several frequencies simultaneously, and totransmit the vibratory movement to the container 110. The frequency ofvibration can range from less than 1 Hz to hundreds kHz, more typicallythe vibration frequency is from about 25 kHz to about 50 kHz. In theembodiment shown in FIG. 1, vibrator 100 is in direct contact withcontainer 110 and thus is directly coupled to container 110.

Container 110 has at least one drug ejection aperture 150 substantiallyopposite vibrator 100 and serving primarily for ejection of drugsubstance 120. However, outside air or gas can also enter containerthrough apertures 150. Further, container 110 has at least one side wallaperture 200 which is not substantially opposite to vibrator 100. Sidewall aperture 200 is not used for ejection of drug substance but permitsair or gas to enter container 110 from outside and thus facilitatesdeaggregation, aerosolization, and ejection of drug substance 120 fromcontainer 110 via drug ejection apertures 150.

Drug substance or substances 120 are provided as a dry powder, but otherforms of drug substance are possible, such as liquid or gas. A singlecomponent drug substance (neat drug) can be used, as well several drugsubstances, or drug substances combined with excipients, such aslactose, or combinations thereof. Other additives, such aspharmaceutically inactive ingredients, de-aggregation agents, etc. canalso be added to the pharmaceutically active drug substance orsubstances.

Container 110 is made of metal, plastic, or composite materials. In oneembodiment of the present invention, container 110 is a blister packmade of cold formed or thermoformed film, with film materials beingpolymer, metallic foil, multi-layer polymer-metallic foil clad films,and barrier coated metallic or polymeric films. In an embodiment of thepresent invention illustrated in FIG. 2, container 110 is a single useblister pack comprising generally conical, pyramidal, semi-spherical,elliptical, or similar top part 111 and flat bottom part 112, whereintop part 111 and bottom part 112 are hermetically sealed to each otherby methods known in the art, including but not limited to bonding,thermal sealing, pressure sealing, ultrasonic sealing, and the like.Area of bonding or sealing 113 is also schematically shown in FIG. 2 inthe area of contact between the top part 111 and the bottom part 112.Vibrator 100 is shown in direct contact with flat bottom part 112 ofcontainer 110.

A number of possible shapes and forms of blister pack or container 110are schematically shown in FIGS. 3A through 3F, including flat topconical shapes (FIGS. 3A, 3D, 3G); cylindrical shapes (FIGS. 3B and 3E),which is also shown in FIG. 4; and semi-spherical or conical shapes(FIGS. 3C, 3F, 3H).

The dimensions of container 110 in one embodiment are from about 1 mm toabout 30 mm in diameter, and from about 1 mm to about 30 mm in height,however larger or smaller containers 110 can be utilized according tothis invention. In another embodiment, the diameter of container 110 isfrom about 3 to about 12 mm, while the height of container 110 is fromabout 3 to about 12 mm.

The dimensions of drug ejection apertures 150 are from about 10 micronsto about 1000 microns, with preferred dimensions from about 50 micronsto about 500 microns. Dimensions of side wall apertures 200 are fromabout 1 micron to about 1000 microns, with preferred dimensions fromabout 25 microns to about 500 microns. In one embodiment of the presentinvention, the total area (cross section) of all drug ejection apertures150 is at least two or more times the total area (cross section) of allside wall apertures 200. In another embodiment of the present invention,the total area (cross section) of all drug ejection apertures 150 is atleast five times the total area (cross section) of all side wallapertures 200.

The number of drug ejection apertures 150 is from 1 to about 10, withnumber of drug ejection apertures 150 in another embodiment being fromabout 3 to about 6. The number of side wall apertures 200 is from 1 toabout 10, with number of side wall apertures 200 in another embodimentbeing from 1 to 2.

In one embodiment of the present invention, vibrator 100 is directlycoupled to container 110 and has substantially the same dimensions asthe dimensions of the container 110 on the coupling surfaces, so thatthe areas of coupling of corresponding surfaces of vibrator 100 andcontainer 110 are substantially the same, as shown in FIGS. 1, 3B, 3C,3D, 3E, 3H, and FIG. 4. In another embodiment of the present invention,shown in FIGS. 2, 3A, 3F, and 3G, dimensions of vibrator 100 are largeror smaller vs. dimensions of the container 110 on the coupling surfaces.Referring now to the embodiments of the present invention shown in FIG.5, vibrator 100 can also be coupled to container 110 via a mechanicalspacer or integral pin 130, as shown in FIG. 5A, or through an air gap140, as shown in FIG. 5B. Vibrator 100 can also be coupled to container110 from a side of the container 110 (embodiment not shown). Vibrator100 can also be disposed directly or partially inside of container 110(embodiment not shown).

The directionality of drug ejection apertures 150 shown in FIGS. 1, 2,3A through 3F, 4, and 5 is substantially normal or perpendicular to thetop surface of vibrator 100, or to the plane of coupling betweenvibrator 100 and container 110, while the directionality of side wallapertures 200 is substantially parallel to top surface of vibrator 100,or to the plane of coupling between vibrator 100 and container 110.However other directionality of apertures 150 and 200 can be used, asshown in FIGS. 3G and 3H, wherein drug ejection apertures 150 are notnormal or perpendicular to the top surface of vibrator 100, or to theplane of coupling between vibrator 100 and container 110, and side wallapertures 200 are not substantially parallel to top surface of vibrator100, or to the plane of coupling between vibrator 100 and container 110.

In operation of an embodiment of the present invention, upon actuationof vibrator 100 and initiation of vibrations, vibration energy istransferred to container 110 whereas drug substance is ejected fromcontainer 110 though at least one drug ejection aperture 150. In oneembodiment of the invention, a synthetic jet of fluid, which can be gasor gas/drug substance mixture, is established through the drug ejectionaperture 150. Synthetic jet is characterized in that the fluid is movingin both directions through aperture 150 with simultaneous formation ofvortices on both sides of the aperture. Synthetic jetting of gas orliquid is known to these skilled in the art and is characterized by highspeed jets of gas or other fluid emanating from an orifice in anenclosed chamber, with fluid entering and exiting the chamber multipletimes through an orifice, so that fluid expelled from the chamber isreplenished by fluid entering the chamber from outside. Reference ismade to US Patent Publication 2005/0183724 by Gumaste and Bowers whichdescribes synthetic jets. Due to gas moving through an orifice in bothdirections, synthetic jets can continue indefinitely. Forming syntheticjets may require establishment of acoustic waves which can beestablished, for example, by piezo-vibrators, and may require acombination of specific parameters, including frequencies, orificedimensions, and container shape and dimensions for establishment ofstrong, sustained, and reproducible synthetic jets.

Referring now to FIG. 6, an embodiment of the present invention inoperation is shown, wherein upon actuation of vibrator 100, side wallaperture 200 permits outside air or gas to enter container 110 (asschematically shown by arrow 205) and thus facilitates efficientejection of drug substance 120 from drug ejection aperture 150 (asschematically shown by arrow 207), increasing speed of ejection andquantities of drug substances capable of being ejected from container110.

Referring now to FIG. 7, an embodiment of the present invention is shownas a schematic representation of a dry powder inhaler, comprisingcontainer 110, vibrator 100, and a flow channel 300. Flow channel 300shown in FIG. 7A is of the cross-flow type, whereby air is flowinggenerally perpendicularly to the direction of drug substance 120ejection from container 110, said direction of the ejection is indicatedby arrow 207. The flow channel 300 shown in FIG. 7B is of theparallel-flow type, whereby air is flowing generally parallel to thedirection of drug substance 120 ejection from container 110, with thedirection of the ejection indicated by arrow 207. A range ofintermediate arrangements of the flow channel 300 and the container 110are possible, whereby air is moving in a more complex pathwayintermediate between parallel flow and cross-flow (embodiment notshown). Upon inhalation by the patient, the air is flowing through theflow channel 300, with air entering as shown by arrows 310 and exitingthe device for inhalation as shown by arrows 320.

Upon actuation of vibrator 100, drug substance 120 is deaggregated,aerosolized, and ejected from the container 110 through drug ejectionaperture 150. The sequence of the deaggregation, aerosolization, andejection of drug substance 120 is not necessarily proceeding in theabove order, wherein all three processes can be occurringsimultaneously, or consecutively in any order depending on theparameters of the process, with the end result being drug substance 120ejected from container 110 through drug ejection aperture 150, andaerosolized drug substance 120 appearing inside flow channel 300.Aerosol of the drug substance 120 is then being picked up by stream ofair 310 outside of container 110, resulting in drug substance 120 beingdelivered to the inhaling patient as shown by arrow 320. The ingress ofoutside air through side wall aperture 200, as shown by arrow 205,facilitates process of deaggregation, aerosolization, and ejection ofdrug substance 120 through drug ejection apertures 150.

Referring now to FIG. 8, an embodiment of the present invention is shownas a schematic of a dry powder inhaler with an inhaler body 480, whereinwithin and also outside of inhaler body 480 are disposed several of theinhaler components, including container 110; vibrator 100; flow channel300; electronic board and circuitry 462 serving to electrically drivevibrator 100 and other electronic components of the inhaler. Battery 464is serving for energizing electronic components and vibrator, saidbattery can be any energy source such as battery pack, which can be aprimary or rechargeable battery, or a fuel cell. Other optionalcomponents of inhaler shown in FIG. 8 are piercing means 400, forpiercing drug ejection apertures and or side wall apertures in containeror blister 110; additional single dose drug containers 450; sensor 420for sensing and detecting inspiration by a user or patient, adapted todetect inspiratory air flow by a user as shown by arrows 310 andinterconnected to electronic circuit 462 to activate vibrator 100 anddrug ejection and aerosolization process. Sensor 420 is preferablycapable, together with electronic board and circuitry 462 of detectingpresence and strength of air flow in the inhaler and optionally thedirectionality of air flow. Patient feedback devices 460 and 466 areproviding sensory feedback to the patient as well as optional dosecounters and indication displays indicating to the user the status ofthe drug delivery and various options. Arrow 320 shows air being inhaledby the patient. Channel 220 provides access of outside air to side wallaperture 200 so that upon actuation of vibrator 100 outside air canenter container 110 as shown by arrow 205.

Referring now to FIG. 9, embodiments of the present invention are shownas schematic representation of dry powder inhalers with a multi-usecontainer 118, wherein drug substance 120 is provided in single use drugpacks 610 and 710 arranged on a carrier tape 620 and 700. The directionof tape movement is shown by arrow 650. In the embodiment shown in FIG.9A, single use drug packs 610 are covered with a lidding tape 630 whichis collected on a spool 635, thus exposing drug substance 120 forejection via drug ejection apertures 150. In another embodiment (notshown), lidding tape 630 is not removed from single use drug packs 610but is perforated before or upon entering multi-use container 118, thusexposing drug substance 120 for ejection via drug ejection apertures150. Multi-use container 118 is in contact with carrier tape 620 throughcompressible gasket or O-ring 600. Upon inhalation by the patient,vibrator 100 is actuated, thus ejecting drug substance 120 throughejection apertures 150. Outside air enters container 118 as shown byarrow 205 via side wall aperture 200, while aerosolized drug substancebeing inhaled by the patient as shown by arrow 320 and air incoming intoflow channel 300 is shown by arrow 310.

Similarly, in FIG. 9B, drug substance 120 is provided in single use drugpacks 710 comprising pockets of tape folded on itself, arranged on acarrier tape 700. The direction of tape movement is shown by arrow 650.Pulling carrier tape 700 results in opening of pockets of tape 710 undermulti-use container 118, with multi-use container 118 in contact withcarrier tape 700 through compressible gasket or O-ring 600. Uponinhalation by the patient, vibrator 100 is actuated, thus ejecting drugsubstance 120 through ejection aperture 150. Outside air enterscontainer 118 as shown by arrow 205 via side wall aperture 200, whileaerosolized drug substance is inhaled by the patient as shown by arrow320 and air incoming into flow channel 300, driven by patient'sinhalation, is shown by arrow 310.

The piercing of apertures in container 110 can be performed immediatelybefore drug substance delivery to the patient. In one embodiment, theinvention operates as follows: the inhaler is activated for use,apertures in the drug container are pierced either simultaneously orsequentially by piercing means 400, or lidding material 630 in case oftape-based drug packs 610 is removed or sheared, or tape-based pouch 710is opened, and then drug substance 120 is aerosolized as the patient isinhaling through the inhaler. In other embodiments, the opening orpiercing of individual drug packs occurs automatically upon inhalationof the patient, through electromechanical or mechanical means, such asspring or electromagnetic actuator, or thermal porator, all optionallyactivated by inhalation detecting sensor 420.

In another embodiment, as illustrated in FIG. 10, multi-use container118 is utilized to deliver drug substance 120, whereby side wallaperture 200 is connected to a source of drug substance 900 via aconduit 910. Source of drug substance 900 has at least two or more dosesof drug substance 120. Quantity of drug substance 120 delivered to apatient is controlled by the timing of the actuation of the device, orby a sensor detecting actual quantity of delivered drug substance 120and controlling actuation of vibrator 100.

Other embodiments and applications of the invention are contemplated.Drug substance for the delivery to the patient can be a vaccine, DNA orRNA fragment, medication for treatment of pain, asthma, emphysema,chronic bronchitis, cystic fibrosis, COPD, diabetes treatment, or anyother medication capable of preventing or treating a disease or relivingsymptoms of a disease when delivered in the aerosolized form to thepatient and having localized and/or systemic effect.

In another embodiment, the present invention is used to deliveraerosolized drug not for inhalation but for intranasal delivery, oraldelivery, eye delivery, or skin surface delivery. In another embodiment,a liquid drug formulation is delivered using the present invention.

EXAMPLE 1

A model inhaler device similar to the designs shown in FIG. 7A, capableof working with either blisters having only drug ejection apertures orboth drug ejection apertures and side wall apertures, was utilized inexperimental testing. The device had integrated electronics and aremovable flow channel. A piezo actuator based on a modified airtransducer manufactured by Murata Electronics, Japan was used as avibrator. The piezo actuator was actuated for 4 seconds and was driven90% of the time at a frequency of 33 kHz and 10% of the time at afrequency of 34.4 kHz, switching between these frequencies at a rate of10 Hz (duty cycle). Alternating voltage of approximately 160-200 voltsgenerated by a fly-back circuit in a step wave-form was used to actuatethe piezo actuator. A blister with approximately semi-spherical top andflat bottom was utilized as a single use container containing model drypowder for aerosolization. The height of the blister was approximately5.5 mm and the diameter of the blister chamber at the base wasapproximately 11 mm, with the shape of the blister similar to the shapeshown in FIG. 3C. The blister was made of aluminum foil coated withpolymeric layers. The top and bottom parts of the blister were thermallysealed to each other. Top (semi-spherical) part of the blister waspierced with 4 drug ejection apertures using metallic needles 320microns in diameter, similar to FIG. 3C, where only two drug ejectionapertures 150 are shown. In some experiments, side wall of the top partof the blister was pierced with at least one side wall aperture 200,similar to FIG. 3C. A needle with diameter of 240 microns was used topierce side wall aperture. A flow of air through the flow channel of thedevice was established at 30 liters per minute (LPM) using a vacuumpump. The blister was filled with variable quantities of a model drypowder, and testing of the gravimetric clearance from the blister wasperformed under varying experimental conditions.

The experimental results are presented in Table 1. As can be seen fromTable 1, unexpected results were obtained, wherein presence of one ormore side wall apertures resulted in a significant increase in the speedof drug ejection and also in the quantity of powder that can beeffectively ejected, compared with conditions without side wallapertures. Comparison of tests 1 and 2; 2 and 2a; 3 and 3a; 7 and 7a; 9and 9a indicates that side wall aperture resulted in very significantincrease in clearance of the powder from the blister, when compared, atthe same conditions, with blisters without side wall apertures. Alsocomparison of tests 4 and 4a; 5 and 5a; 6 and 6a indicates that withoutpiezo actuation, no appreciable clearance was detected even when sidewall apertures were present. Side wall apertures enabled very highgravimetric clearance of regular quantities of powder from the blister,i.e. quantities of the order of 3-6 mg, but also very large quantitiesof powder, for instance of the order of 15-20 mg and as high as 37 mg,wherein practically no powder ejection can be observed from blistersunder same conditions without side wall apertures, as demonstrated bytests 3 and 3a; 7 and 7a; and 8 and 9a. It was visually detected thatthe clearance of the blisters with side wall apertures occurred fast,sometimes in less than a second, and faster vs. blisters without sidewall apertures, which have not completely cleared even in 4 seconds. Itwas not seen that any appreciable amount of powder was ejected from sidewall apertures during the testing performed.

TABLE 1 Powder cleared Powder in from the blister, blister, Gravimetric## mg Apertures in blister Dosing Procedure mg Clearance % Testconditions 1* 5.037 4 drug ejection Piezo actuated, Vacuum 4.807 95.4%Blister with side wall apertures & side wall pump actuated apertureactuated with piezo aperture pierced 2 4.204 4 drug ejection Piezoactuated, Vacuum 1.035 24.6% Blister without side wall apertures piercedpump actuated aperture actuated with piezo 2a** 3.169 2 side wallapertures Piezo actuated, Vacuum 3.061 96.6% Blister #2 repeated after 2and 4 drug ejection pump actuated side wall apertures pierced aperturespierced 3 19.028 4 drug ejection Piezo actuated, Vacuum 1.051 5.5%Blister without side wall apertures pierced pump actuated apertureactuated with piezo 3a* 17.977 Side wall aperture and 4 Piezo actuated,Vacuum 17.903 99.6% Blister #3 repeated with side drug ejectionapertures pump actuated wall aperture pierced 4* 12.215 Side wallaperture and 4 Vacuum pump actuated 0.634 5.2% Blister with side walldrug ejection apertures for 20 seconds aperture exposed to pump piercedair flow for 20 s; no piezo actuation 4a* 11.581 Side wall aperture and4 Piezo actuated, Vacuum 11.483 99.2% Blister #4 repeated with drugejection apertures pump actuated piezo actuation pierced 5* 7.388 Sidewall aperture and 4 Vacuum pump actuated 0.072 1.0% Blister with sidewall drug ejection apertures for 20 seconds aperture exposed to air flowpierced for 20 s; no piezo actuation 5a* 7.316 Side wall aperture and 4Piezo actuated, Vacuum 7.22 98.7% Blister #5 (with side wall drugejection apertures pump actuated aperture) repeated with pierced piezoactuation 6* 5.147 Side wall aperture and 4 Vacuum pump actuated 0.0250.5% Blister with side wall drug ejection apertures for 20 secondsaperture exposed to air flow pierced for 20 s; no piezo actuation 6a*5.122 Side wall aperture and 4 Piezo actuated, Vacuum 5.015 97.9%Blister #6 (with side wall drug ejection apertures pump actuatedaperture) repeated with pierced piezo actuation 7 17.139 4 drug ejectionPiezo actuated, Vacuum 1.67 9.7% Blister without side wall aperturespierced pump actuated aperture actuated with piezo 7a* 15.469 Side wallaperture and 4 Piezo actuated, Vacuum 14.482 93.6% Blister #7 repeatedwith side drug ejection apertures pump actuated wall aperture pierced 8*23.949 Side wall aperture and 4 Piezo actuated, Vacuum 23.636 98.7%Blister with side wall drug ejection apertures pump actuated apertureactuated with piezo pierced 9 37.582 4 drug ejection Piezo actuated,Vacuum 0.229 0.6% Blister without side wall apertures pierced pumpactuated aperture actuated with piezo 9a* 37.353 Side wall aperture and4 Piezo actuated, Vacuum 37.105 99.3% Blister #9 repeated with side drugejection apertures pump actuated wall aperture pierced *Tests with atleast one Side Wall Aperture

EXAMPLE 2

Experimental testing was performed using an experimental setup similarto the setup described in Example 1, but with a proprietary piezoactuator G9 tuned to resonant frequency of 34.5 kHz, driven 90% of thetime at a frequency of 34 kHz and 10% of the time at a frequency of 35kHz, switching between these frequencies at rate of 10 Hz (duty cycle).Alternating voltage of approximately 160-200 volts generated by afly-back circuit in a step wave-form was used to actuate the piezoactuator. A model drug powder (insulin) was used, and demonstrated avery good clearance from the blister. In the experiment, a quantity ofdrug powder considerably larger vs. typical quantities of 1-3 mg perblister was used. In two tests a blister containing 5 mg of drug powderand having a side wall aperture, in addition to four drug ejectionapertures demonstrated 94.6% and 95.9% clearance of powder from theblister during piezo actuation time of 4 seconds. It was observed thatthe actual clearance time was lower than 4 seconds of piezo actuationtime. Thus unexpectedly, much larger quantity of powder is cleared fromthe blister having a side wall aperture vs. typically seen with the sameblisters but without side wall aperture, which achieved clearances ofaround 80 to 95% only when filled with much lower quantities of insulin,i.e. up to about 2 mg.

EXAMPLE 3

Using an experimental setup similar to the setup described in Example 2,a test of a model drug powder blend with lactose was performed with verygood clearance, wherein 6 mg of the blend cleared with 97.5% gravimetricclearance from a blister having a side wall aperture. The same blistersbut without side wall aperture, demonstrated much lower gravimetricclearances.

EXAMPLE 4

Experiments were performed in a setup similar to the experimental setupdescribed in Example 1, but with a non-modified Murata Electronics airtransducer serving as a piezo actuator, having resonant frequency of 40kHz. Piezo actuators with other resonant frequencies can also be used,typically in the range from 30 to 45 kHz. Flow of air through the devicewas established at 28 LPM using a vacuum pump. Plastic cone-shaped topand cone-shaped, flat top blisters with flat metal foil bottom wereutilized as single use containers containing model powder foraerosolization, similar to the blisters depicted in correspondinglyFIGS. 3F and 3D. The blisters with cone shaped top had straight conetop, while cone-shaped, flat top blisters had a cone top coming to aflat end with the diameter of approximately 2 mm. The height of theblisters was approximately 4.5 mm and the diameter of the blisterchamber at the base was approximately 8 mm. Blister tops were made bythermoforming of PVC or PETG plastic and thermally sealed to the blisterbottom, made of polymer-clad aluminum foil. The top part of the blisterswas pierced with 3 holes using metallic needles 240 microns in diameter,thus forming drug ejection apertures, similar to FIG. 3D. In someexperiments, the side wall of the conical part of the blister waspierced with at least one side wall aperture, similar to FIGS. 3A, 3B,3C. A needle with a diameter of 240 microns was used to pierce the sidewall aperture. The results of these experiments are presented in Table2.

TABLE 2 Piezo Powder Blister Powder in the actuation cleared fromGravimetric ## Shape blister, mg time blister, mg Clearance % Testconditions 10* cone shaped 4.006 4 sec 3.902 97.4% Side Wall Aperture11* cone shaped 5.514 4 sec 5.454 98.9% Side Wall Aperture 12 coneshaped 3.764 4 sec 2.516 66.8% No Side Wall Aperture 13* Cone 6.769 2sec 6.617 97.8% Side Wall shaped flat Aperture top 14 Cone 3.194 2 sec2.984 93.4% No Side Wall shaped flat Aperture top *Tests with at leastone Side Wall Aperture

As can be seen from the Table 2, unexpected results were obtained,wherein a significant increase in the speed of powder ejection and alsoquantity of powder that can be ejected form a blister was experimentallyobserved, compared with conditions without side wall apertures.

EXAMPLE 5

Testing of the air flow in and out of the blister having several drugejection apertures and at least one side wall aperture was performed.Experimental setup was similar to the setup described in Example 1, butno powder was present in the blisters in these experiments and no airflow was established using a vacuum pump. In addition, a plasticcapillary tubing was connected to the side wall aperture from outside.In the first test, when the blister was intermittently actuated with thepiezo actuator, a sensitive lightweight flag was observed moving towardsthe inlet of the plastic capillary tubing thus registering the vacuumand/or air flow through the capillary tubing and through side wallaperture into the blister, while air is being ejected from the drugejection apertures on top of the blister.

In the second test, a second lightweight flag was placed above drugejection apertures on top of the blister, said lightweight flag wasobserved moving upwards detecting jets of air emanating from drugejection apertures. At the same time the first sensitive lightweightflag was observed moving towards the inlet of the plastic capillarytubing thus registering the vacuum and/or air flow through the capillarytubing and through the side wall aperture into the blister, said firstflag being suctioned to the plastic capillary tubing inlet and blockingit. It was further observed that when said first flag was manuallyremoved from blocking the plastic capillary tubing inlet and thus fromblocking the air intake into the side wall aperture, the second flagindicated notable increase in air jets emitted from the drug ejectionapertures on top of the blister. Thus is appears that side wall aperturehelped increasing the jetting of air emanating from the blister byproviding air supply into the blister.

EXAMPLE 6

Experiments were performed in a setup similar to the experimental setupdescribed in Example 2, but without activating a vacuum pump and drivingany air through the flow channel of the experimental setup. A modellactose dry powder was used in the experiments. In a blister without theside wall aperture, filled with 6.390 mg of lactose, a clearance of only28.4% was observed. In blisters with side aperture, filled with 5.013and 6.560 mg of lactose powder, a clearance of correspondingly 80.8% and93.4% was observed. Thus unexpected results were obtained, wherein asignificant increase in the speed of powder ejection and also quantityof powder that can be ejected was experimentally observed, compared withconditions without side wall apertures.

While the present invention has been particularly described, inconjunction with specific preferred embodiments, it is evident that manyalternatives, modifications and variations will be apparent to thoseskilled in the art in light of the foregoing description. It istherefore contemplated that the appended claims will embrace any suchalternatives, modifications and variations as falling within the truescope and spirit of the present invention.

1. An dry powder inhaler, comprising: an inhaler body including a spacefor accommodating a container containing a dry powder, a vibratoryelement, a flow channel, and electronic circuitry to electrically drivethe vibratory element, wherein said container has a flat bottom wall, atop wall and a side wall bridging the top wall and the bottom wall; atleast one drug substance ejection aperture in the top wall of saidcontainer; and at least one air intake aperture in the side wall of saidcontainer; wherein said vibratory element has a flat surface adapted tocouple to the flat bottom of said container to vibrate said containerand to eject said drug substance from said container through said atleast one drug substance ejection aperture and into said flow channeladapted to be inhaled by a patient.
 2. The inhaler as in claim 1,wherein said drug substance is deaggregated and aerosolized when ejectedfrom said container.
 3. The inhaler as in claim 1, wherein said drugsubstance is ejected from said container through synthetic jetting. 4.The inhaler as in claim 1, wherein said container is sized to empty ofsaid drug substance in less than approximately 2 seconds.
 5. The inhaleras in claim 1, wherein said drug substance is ejected from saidcontainer with gravimetric clearance from approximately 80% of said drugsubstance to approximately 100% of said drug substance.
 6. The inhaleras in claim 1, wherein said drug substance is present in said containerin quantity from approximately 1 mg to approximately 100 mg.
 7. Theinhaler as in claim 1, wherein said drug substance is selected from thegroup consisting of a drug powder, a mixture of a drug powder with anexcipient, a mixture of two or more pharmaceutically active drug powdermaterials, a mixture of two or more pharmaceutically active drug powdermaterials with an excipient, and a combination thereof.
 8. The inhaleras in claim 1, wherein said at least one air intake aperture is roundand has a diameter from about 25 microns to about 400 microns.
 9. Theinhaler as in claim 1, wherein said at least one air intake aperture isround, triangular, square, or polygonal in shape.
 10. The inhaler as inclaim 1, wherein said container comprises a foil blister, a foil pouch,a plastic blister, or a combination thereof.
 11. The inhaler as in claim1, wherein said container is reusable.
 12. The inhaler as in claim 1,wherein said container is formed from a metal, a metal foil, apolymer-coated metal foil, a polymer film, a barrier coated polymerfilm, a polymer, a polymer laminate, and a combination thereof.
 13. Theinhaler as in claim 1, wherein said vibratory element is a piezoactuator, a piezo transducer, or a piezo vibrator.
 14. The inhaler as inclaim 1, further comprising a driver for driving said vibratory elementto vibrate at ultrasonic frequencies.
 15. The inhaler as in claim 1,wherein said container has one air intake aperture and four drugsubstance ejection apertures.
 16. The inhaler as in claim 1, having atleast two apertures in the top wall of the container.
 17. The inhaler asin claim 1, wherein said at least one aperture in the top wall of thecontainer is in communication with an air stream in said flow channeladapted to be inhaled by a patient, wherein upon vibrating said drug isejected from said at least one aperture in the top wall and picked up bysaid air stream adapted to be inhaled by said patient.
 18. The inhaleras in claim 1, wherein the total area of ejection aperture(s) in the topwall of the container is at least two times the total area of our intakeaperture(s) in the side wall(s) of the container.
 19. The inhaler as inclaim 18, wherein the total area of ejection aperture(s) in the top wallof the container is at least five times the total area of air intakeaperture(s) in the side wall(s) of the container.